Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Research Scope

Technological innovations in chemical synthesis, cheminformatics, structural biology, and high throughput bioactivity and drug property assays have allowed rapid discovery of novel, small-molecule probes for the study of disease-related biological processes and mechanisms in academic environments.

Through this Notice of Funding Opportunity (NOFO), NIMH, NIDA, NEI and/or NIA encourage applications to advance the discovery of small molecule chemical probes that would enable, by modulating the function of a novel biological target, mechanistic questions to be addressed in animal studies. The NIH aims to stimulate research in 1) discovery and development of a novel in vivo chemical probes for their potential use in understanding biological processes relevant to the missions of the participating NIH Institutes, and 2) use of chemical probes to discover and/or validate novel biological targets that will inform studies of brain disease mechanisms. Emphasis will be placed on research that provides new insight into important disease-related biological targets and biological processes. For example, applications may involve emerging therapeutic targets and mechanisms for the discovery of chemical probes that may lead to further development of therapeutics or provide insight into the biology of relevant diseases.

This program creates an opportunity for integrated research in biology and chemistry on structure-activity relationships (SAR) of novel compounds through an iterative and parallel optimization process, to advance the successful development of in vivo chemical probes. Applicants to this NOFO should have, in hand, the starting compounds ( validated hits ) for chemical optimization and bioassays for testing new analog compounds. The iterative bioassay and chemical optimization cycles may encompass:

• In vitro cellular and tissue activities (potency, selectivity assessment of on-target and off-target effects in cells, specificity, etc.).
• In vitro structural, physicochemical, and biochemical properties (solubility, stability, membrane permeability (Caco-2/MDR1-MDCK/PAMPA), protein binding, microsome stability, metabolite identification, CYP inhibition, etc.).
• In vivo pharmacokinetics (PK) with absorption, distribution, metabolism, excretion (ADME) and toxicity.
• In vivo efficacy.

The above-mentioned areas of investigation are representative and not meant to be all-inclusive.

The main emphasis of projects submitted under this NOFO should be on chemical probes development rather than drugs or therapeutic discovery, the latter of which are beyond the scope of this NOFO.

Applications Not Responsive to this NOFO.

Applications on the following research topics are not responsive to this NOFO and will be withdrawn prior to review:

• Projects proposing the development of phenotypic chemical probes.
• Projects proposing the development of drugs or therapeutic discovery.
• Projects seeking resources for later-stage drug development.
• Projects proposing extensive studies required for the preclinical or clinical development of candidate therapeutics, such as IND-directed toxicological testing and Good Manufacturing Practices (GMP) synthesis.

Institute Interests

NIMH:

NIMH is interested in applications proposing the optimization of chemical probes aimed at novel molecular, cellular, or circuit targets relevant to mental disorders, especially treatment-resistant depression, bipolar disorder, schizophrenia, Post-Traumatic Stress Disorder (PTSD), HIV-induced Central Nervous System (CNS) dysfunction and autism spectrum disorder (see From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness. Studies aimed at the development of new ligands for targets where a high-quality probe or therapeutic already exists are generally of lower priority.

Projects at early stages of drug discovery and development should consider Assay Development and Screening for Discovery of Validated Chemical Hits PAR-23-168 (R01), the Drug Discovery for Nervous System Disorders PAR-22-031 (R01) and PAR-22-032 (R21), and the National Cooperative Drug/Device Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Substance Use Disorders, or Alcohol Use Disorder PAR-22-144 (U19) and PAR-22-143 (U01). Projects for developing commercially focused products should consider applying to the NIMH SBIR/STTR Programs. Projects at the early clinical trials phase should consider the NIMH SBIR Program or the First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders PAR-21-133 (U01). Details on these and additional notices of funding opportunites and therapeutic discovery resources are listed on the NIH/NIMH Therapeutics Discovery Research web page.

The purpose of in vivo measures should be carefully considered. Given the lack of predictive preclinical behavioral measures of clinical efficacy for mental disorders, the NIMH is particularly interested in the development and testing of novel interventions that target operationally defined, biologically linked functional domains whose disruption is hypothesized to drive functional deficits in mental disorders. For example, NIMH Research Domain Criteria (RDoC) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures, and clinical subjects. Intervention targets related to RDoC constructs and underlying circuits are of interest for this NOFO, but other, biologically relevant targets are also of interest.

Scientific rigor and transparency in conducting biomedical research are key to the successful application of knowledge toward improving health outcomes. In support of this important goal, investigators must follow NIH Guidance on addressing rigor and reproducibility in grant applications.

Further information on NIMH research priorities can be found in the NIMH Strategic Plan, Strategic Research Priorities, and the Interventions Workgroup Report. Applicants are strongly encouraged to discuss applications with NIMH staff listed in Section VII prior to submission to determine the alignment of the planned studies with NIMH priorities and to assess whether this or other NIMH funding opportunities are most appropriate.

NIDA:

NIDA is interested in funding projects that will lead to the discovery and early development of chemical probes for the treatment of substance use disorders (SUDs). Application topics might include, for example, target identification/validation, assay development, lead discovery and/or preliminary, iterative chemical probe development (SAR). Chemical probes could be used as: (i) tools for elucidating SUD-related mechanistic processes, or (ii) future lead pharmacotherapeutic candidates for the treatment of SUDs. Projects that are further along in the medication development pipeline (e.g., lead optimization or preclinical IND-preparatory studies) should consider applying to alternative NOFOs, such as PAR-22-202 . Investigators are strongly encouraged to discuss potential research plans with the scientific contact below prior to submission.

NIA:

NIA is interested in High-Throughput Screening (HTS) assays and chemical probes that are relevant to the process of normal aging (including normal cognitive aging) and age-related diseases and conditions in a variety of tissues. Examples include Mild Cognitive Impairment (MCI), Alzheimer’s disease and other dementias of aging, osteoporosis, sarcopenia, and other age related changes that occur during the human lifespan. NIA is particularly interested in assays and chemical probes that will be useful in identifying new therapeutic targets and, novel therapeutic and imaging agents. NIA is also interested in assays to screen for compounds that affect protective factors or processes that may contribute to slowing or reversing the progression of age-related adverse molecular, biochemical, genetic, cellular, or physiological changes that contribute to multiple age-related diseases, and which hence could contribute to longer health span.

NEI:

The NEI is especially interested in applications to develop novel, clinically relevant targets, which can be transformed into therapeutics for the treatment of visual diseases and disorders. Appropriate research areas include, but are not limited to, inflammatory, vascular, and degenerative diseases of the eye, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, ocular infections, corneal wound healing, and dry eye syndrome. Proposed projects should be relevant to NEI’s mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will lead to sight-saving treatments, reduce visual impairment and blindness, and improve the quality of life for people of all ages.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations

All page limitations described in the How to Apply Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: In the Research Strategy section, applicants should address the following topics as they pertain to the research project proposed:

1. Biological Target. Address the novelty and significance of the biological target or biological process. Clearly describe any known small molecule modulators and the need for better small molecule modulators against the intended biological target or biological process.

2. Validated Hits. Applicants to this NOFO should have, in hand, the starting compounds ( validated hits ) for chemical optimization and bioassays for testing new analog compounds. For purposes of this initiative, a hit is defined as a compound that has the desired activity in a compound screen and whose activity is confirmed upon retesting in orthogonal assays. Various approaches using in silico, in vitro, ex vivo, or in vivo assays may be adopted toward pursuing a validated hit, including application of machine learning (ML) at each step of the hit discovery stage, spanning from hit identification to hit optimization, use of generative ML models in de-novo design of chemical structures with desired properties, ligand-based or structure-based virtual screening and computational hit expansion, high throughput screening (HTS) of a large collection of structurally diversified or privileged compounds, and use of ML in the design of new molecules employing phenotypic and high content screening data and assessing their potency, selectivity, and binding affinity, and use of ML models for predicting bioactivity and ADMET parameters of compounds.

For a hit compound to be accepted as the starting point of this program, it should have the following well-characterized properties:

• elicit a reproducible response in at least two orthogonal assay types and elicit a dose-response over a hundred-fold concentration range.
• be analytically validated in terms of integrity and purity (e.g., use of resynthesized powder sample of high purity in the preliminary assays).
• demonstrate adequate potency.
• demonstrate the adequate potential for selectivity.
• possess a tractable starting point of chemical optimization with no obvious major chemical liabilities.

To enhance the likelihood of success of the project, the parallel optimization of multiple validated hits is highly encouraged.

3. Assays. A cascade of in vitro and in vivo assays needs to be in place to efficiently test analog compounds derived from the submitted hits. The applicants are expected to perform in vitro and in vivo SAR assays related to their research fields. The in vitro SAR assays may include target-, pathway-, and phenotype-based assays. Some examples are a) target-based biochemical or cellular assays that measure activities of enzymes, receptor-ligand bindings, protein-protein interactions, ion channels, transporters, nuclear receptors, and other new targets emerging from genetic and other omics research in model systems and in human diseases; b) cell- or organism-based assays that detect phenotypic changes that may involve unidentified molecular targets; and c) non-traditional targets of interest such as nucleic acids, protein folding, polymorphic gene products, post-transcriptional editing or splicing of gene products, and protein or RNA stabilization. The assay detection methods may include fluorescence, luminescence, absorbance, fluorescence resonance energy transfer (FRET), time-resolved fluorescence resonance energy transfer (TR-FRET), fluorescence polarization, flow cytometric measurements, fluorescence imaging, bioluminescence resonance energy transfer (BRET), AlphaScreen, scintillation proximity assay (SPA), electrophysiology, and varieties of biophysical readouts. Assays adaptable to microtiter plates (96-, 384-well plates) are advantageous in the rapid generation of assay data to enhance SAR iteration efficiency.

Demonstrate that the proposed assays are adequate for the iterative study of structure-activity relationships and that the proposed assay reagents and protocols are in place and will be readily implemented.

The in vivo activity assays may be proof-of-concept assays using one, well-characterized animal species model. Recognizing that very few disease models are clinically validated, applicants are expected to present a convincing argument that the models selected, endpoints measured, and levels of activity observed are likely to be clinically relevant. These preclinical "proof-of-concept" studies must be sufficiently powered, controlled, and replicated to lend a high degree of confidence to the results.

4. Probe criteria. (1) Define the specific criteria that a compound must meet to be considered a probe for the project, (2) provide thorough literature and informatics analysis of any known small molecule probe for the intended biological target or biological process, and (3) provide evidence that the validated hit to be optimized is engaging its target in vivo.

5. Critical path. Include a flow diagram to outline all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines, including but not limited to iterative chemical optimization and bioassays to be implemented, alternative approach (e.g., computational docking) to ensure the success of the probe discovery, in vivo pharmacokinetic/pharmacodynamic assays to characterize chemical probes, the study of structure-activity relationships, assay and chemistry responsibilities of each party involved.

6.Future plan. Include a plan to briefly describe existing, and potential follow-up assays to advance chemical probes in the future.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

• For the purpose of this NOFO, the following data generated or developed under this NOFO are expected to be released to PubChem, consistent with achieving the goals of this program:
  • (1) all assay data,
  • (2) protocols for assays implemented,
  • (3) the chemical structure of compounds tested in assays, and
  • (4) synthetic protocols of chemicals.

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded by NIMH under this NOFO are expected to share those data via the National Institute of Mental Health Data Archive (NDA; see NOT-MH-23-100). Established by the NIH, NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this NOFO are expected to use these technologies to submit data to NDA.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission. The NDA website provides two tools to help investigators develop appropriate strategies: 1) the NDA Data Submission Cost Model which offers a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent available from the NDA's Data Contribution page. Investigators are expected to certify the quality of all data generated by grants funded under this NOFO prior to submission to NDA and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see NDA Sharing Regimen for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied. For more guidance on submitting data to NDA, refer to the NDA Data Management and Sharing Plan on the NDA website. NDA staff will work with investigators to help them submit data types not yet defined in the NDA Data Dictionary.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or more in Direct Costs as described in the SF424 (R&R) Application Guide.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the HHS Office for Civil Rights website.

HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Enrique L. Michelotti, Ph.D.
NIMH - NATIONAL INSTITUTE OF MENTAL HEALTH
Telephone: 301-443-5415
Email: michelottiel@mail.nih.gov

Paul G. Grothaus, Ph.D.
NIA - NATIONAL INSTITUTE ON AGING
Division of Neuroscience
Phone: 3015551212
E-mail: grothausp@mail.nih.gov

Paekgyu Lee
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 435-8164
E-mail: paek.lee@nih.gov

Subramaniam Ananthan, Ph.D.
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-435-2199
E-mail: sam.ananthan@nih.gov

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: weissh@mail.nih.gov

Jeni Smits
NIA - NATIONAL INSTITUTE ON AGING
E-mail: jeni.smits@nih.gov

Karen Robinson Smith
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8178
E-mail: kyr@nei.nih.gov

Pamela G Fleming
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.